Heat treatment-induced autophagy promotes breast cancer cell invasion and metastasis via TGF-ß2-mediated epithelial-mesenchymal transitions.

Background: Insufficient thermal ablation can accelerate malignant behaviors and metastases in some solid tumors, and epithelial-mesenchymal transition (EMT) and autophagy are involved in tumor metastasis. It has been found that TGF-ß2 which belongs to the family of transforming growth factors often associated with cancer cell invasiveness and EMT. However, whether the interactions between autophagy and TGF-ß2 induce EMT in breast cancer (BC) cells following insufficient microwave ablation (MWA) remains unclear. Methods: BC cells were treated with sublethal heat treatment to simulate insufficient MWA, and the effects of heat treatment on the BC cell phenotypes were explored. CCK-8, colony formation, flow cytometry, Transwell, and wound healing assays were performed to evaluate the influence of sublethal heat treatment on the proliferation, apoptosis, invasion, and migration of BC cells. Western blotting, real-time quantitative PCR, immunofluorescence, and transmission electron microscopy were carried out to determine the changes in markers associated with autophagy and EMT following sublethal heat treatment. Results: Results showed that heat treatment promoted the proliferation of surviving BC cells, which was accompanied by autophagy induction. Heat treatment-induced autophagy up-regulated TGF-ß2/Smad2 signaling and promoted EMT phenotype, thereby enhancing BC cells' migration and invasion abilities. An increase or decrease of TGF-ß2 expression resulted in the potentiation and suppression of autophagy, as well as the enhancement and abatement of EMT. Autophagy inhibitors facilitated apoptosis and repressed proliferation of BC cells in vitro, and thwarted BC cell tumor growth and pulmonary metastasis in vivo. Conclusion: Heat treatment-induced autophagy promoted invasion and metastasis via TGF-ß2/Smad2-mediated EMTs. Suppressing autophagy may be a suitable strategy for overcoming the progression and metastasis of residual BC cells following insufficient MWA.

An extensive bioinformatics study on the role of mitochondrial solute carrier family 25 in PC and its mechanism behind affecting immune infiltration and tumor energy metabolism.

BACKGROUND: Several metabolic disorders and malignancies are directly related to abnormal mitochondrial solute carrier family 25 (SLC25A) members activity. However, its biological role in pancreatic cancer (PC) is not entirely understood. METHODS: The lasso method was used to create a novel prognostic risk model for PC based on SLC25A members, and its roles in tumor immunology and energy metabolism were explored. Furthermore, co-expression networks were constructed for SLC25A11, SLC25A29, and SLC25A44. Single-cell RNA sequencing (ScRNA-seq) revealed the distribution of gene expression in PC. Tumor immune infiltration was examined with the TIMER database. Lastly, drug sensitivity was investigated, and co-transcriptional factors were predicted. RESULTS: In the present study, a novel prognostic risk model was established and validated for PC based on SLC25A members. The high-risk group had a lower activation of oxidative phosphorylation and a more abundant immune infiltration phenotype than the low-risk group. According to co-expression network studies, SLC25A11, SLC25A29, and SLC25A44 were involved in the energy metabolism of PC and prevented tumor growth, invasion, and metastasis. ScRNA-seq research also pointed to their contribution to the tumor microenvironment. Moreover, the recruitment of numerous immune cells was positively correlated with SLC25A11 and SLC25A44 but negatively correlated with SLC25A29. Additionally, the sensitivity to 20 Food and Drug Administration-approved antineoplastic medicines was strongly linked to the aforementioned genes, where cisplatin sensitivity increased with the up-regulation of SLC25A29. Finally, the Scleraxis BHLH Transcription Factor (SCX) and other proteins were hypothesized to co-regulate the mRNA transcription of the genes. CONCLUSION: SLC25A members are crucial for tumor immune and energy metabolism in PC, and SLC25A11, SLC25A29, and SLC25A44 can be used as favorable prognostic markers. The use of these markers will provide new directions to unravel their action mechanisms in PC.

FAM81A identified as a stemness-related gene by screening DNA methylation sites based on machine learning-accessed stemness in pancreatic cancer.

Aim: We thoroughly discuss the interaction between the stemness index and DNA methylation in pancreatic cancer (PC). Materials & methods: First, the stemness indices of PC (denoted mRNAsi and mDNAsi) were calculated using a one-class logistic regression machine-learning algorithm. Second, we screened the central methylation sites associated with stemness and screened out the key genes. We investigated the DNA methylation regulators associated with the key genes. Finally, using CIBERSORT and TIMER, we assessed the influence of stemness indexes and key genes on PC microenvironment formation. Results: In this study we quantified the stemness indices for PC and screened 20 related central DNA methylation sites. Further analysis of the methylation site cg22687244, located in the 3' UTR, revealed that it promoted the expression of the key gene FAM81A. We show that FAM81A may be regulated by DNA methylation regulators. Furthermore, immune cells were found to be more abundant in PC microenvironments with high expression of FAM81A. Conclusion: We report for the first time that the 3' UTR methylation of FAM81A is closely related to PC stemness and contributes to tumor immune infiltration. Therefore FAM81A may serve as a potential marker to guide the treatment of PC.

Factors Associated with Shoulder Range of Motion After Arthroscopic Rotator Cuff Repair: A Hospital-Based Prospective Study.

OBJECTIVE: To assess the factors associated with outcomes of arthroscopic surgical repair of rotator cuff tears (RCTs). METHOD: This prospective study recruited patients, at least 18 years old, who underwent arthroscopic rotator cuff repair for full-thickness RCTs at the First People's Hospital of Hangzhou Xiaoshan between July 2019 and October 2020. Patient demographics, lifestyle habits, and medical histories were collected preoperatively; RCT sizes and affected tendons were determined intraoperatively. Outcomes were assessed by shoulder range of motion (ROM) determinations 1.5 and 3 months postoperatively. The factors associated with ROM were determined using a binary logistic regression analysis, and the results were expressed as adjusted relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: A total of 132 patients with RCTs underwent arthroscopic surgery. Five were lost to follow-up, leaving 127 patients (mean age, 59 years; 58.3% women) who were included in the study analysis. The majority of the patients (54.5%) had RCTs that were classified as large or massive, and approximately 20% had tears involving multiple tendons; 80.3% of the patients had tears involving only a single tendon. Moreover, 29.9% of the patients had hypertension and 11.0% had diabetes. Among the patients, 23.0% were smokers and 34.6% drank alcohol. According to the multivariate analysis, none of the assessed factors were associated with shoulder ROM at the 1.5-month follow-up. At the 3-month follow-up, RCTs involving a single tendon demonstrated 3-fold better abduction (RR = 4.00; 95% CI, 1.30-12.33; P = 0.016) and 3.15-fold better internal rotation (RR = 3.15; 95% CI, 1.19-8.36; P = 0.021) than did RCTs involving multiple tendons. Patients who did not drink alcohol demonstrated 6.08-fold better anteflexion (RR = 7.08; 95% CI, 2.11-23.73; P = 0.002) and nearly 4-fold better abduction (RR = 4.97; 95% CI, 1.62-15.23; P = 0.005) than patients who drank alcohol. CONCLUSION: To improve outcomes, the results indicate that more targeted measures should be directed toward patients with multiple-tendon RCTs and that preoperative alcohol abstinence education is needed for patients with RCTs.

Clinical Observation on the Treatment of Rotator Cuff Injury with Modified Buyang Huanwu Decoction and Rotator Cuff Repair.

In this paper, we have evaluated the clinical efficacy of rotator cuff surgery combined with Chinese medicine Buyang Huanwu Decoction (adding medicine) in the treatment of patients with rotator cuff injury. For this purpose, sixty patients with rotator cuff injury and shoulder arthroscopic surgery were selected in this hospital (where 57 cases were finally screened). The patients were divided into a control group (28 cases) and a study group (29 cases) by the envelope method. The control group received conventional treatment after the operation, whereas the study group was combined with Buyang Huanwu Decoction after the operation. The clinical efficacy of the two groups, particularly after treatment, was compared in terms of self-care ability and Constant-Murley scores before and after treatment, that is, 4 w, 8 w, and 12 w. The total effective rate of treatment in the study group was significantly higher than that of the control group after 4 weeks of treatment (P < 0.05). There was no significant difference in the FIM self-care scores of the two groups before treatment (P > 0.05). In the study group patients, after treatment for 4 w and 8 w, the FIM self-care score was significantly improved (P < 0.05). The FIM self-care score of the patients in the study group, after 12 w of treatment, had no significant difference compared with the control group (P > 0.05). The Constant-Murley scores of the two groups were compared before treatment where no significant difference is observed (P > 0.05) and the Constant-Murley score of the study group patients was significantly higher than that of the control group, after 4 w and 8 w treatment (P < 0.05). Additionally, Constant-Murley score of the study group was not significantly higher than that of the control group after 12 w of treatment difference (P > 0.05). The proposed combined treatment program has value of promotion and implementation in the clinical treatment of patients with rotator cuff injury.

Establishment of a Prognostic Model for Hepatocellular Carcinoma Based on Endoplasmic Reticulum Stress-Related Gene Analysis.

Hepatocellular carcinoma (HCC) is one of the most common types of cancer worldwide and its incidence continues to increase year by year. Endoplasmic reticulum stress (ERS) caused by protein misfolding within the secretory pathway in cells and has an extensive and deep impact on cancer cell progression and survival. Growing evidence suggests that the genes related to ERS are closely associated with the occurrence and progression of HCC. This study aimed to identify an ERS-related signature for the prospective evaluation of prognosis in HCC patients. RNA sequencing data and clinical data of patients from HCC patients were obtained from The Cancer Genome Atlas (TCGA) and The International Cancer Genome Consortium (ICGC). Using data from TCGA as a training cohort (n=424) and data from ICGC as an independent external testing cohort (n=243), ERS-related genes were extracted to identify three common pathways IRE1, PEKR, and ATF6 using the GSEA database. Through univariate and multivariate Cox regression analysis, 5 gene signals in the training cohort were found to be related to ERS and closely correlated with the prognosis in patients of HCC. A novel 5-gene signature (including HDGF, EIF2S1, SRPRB, PPP2R5B and DDX11) was created and had power as a prognostic biomarker. The prognosis of patients with high-risk HCC was worse than that of patients with low-risk HCC. Multivariate Cox regression analysis confirmed that the signature was an independent prognostic biomarker for HCC. The results were further validated in an independent external testing cohort (ICGC). Also, GSEA indicated a series of significantly enriched oncological signatures and different metabolic processes that may enable a better understanding of the potential molecular mechanism mediating the progression of HCC. The 5-gene biomarker has a high potential for clinical applications in the risk stratification and overall survival prediction of HCC patients. In addition, the abnormal expression of these genes may be affected by copy number variation, methylation variation, and post-transcriptional regulation. Together, this study indicated that the genes may have potential as prognostic biomarkers in HCC and may provide new evidence supporting targeted therapies in HCC.

Expression and prognostic analyses of SCAMPs in pancreatic adenocarcinoma.

Due to the difficulties in early diagnosis of pancreatic adenocarcinoma (PAAD), many patients fail to receive optimal therapeutic regimens. The Secretory-Carrier-Membrane-Proteins (SCAMPs) are known to be dysregulated in a range of human diseases due to their characterized roles in mammalian cell exocytosis inferred from their functions as integral membrane proteins. However, the expression and prognostic value of SCAMPs in PAAD is poorly characterized. We compared cancer vs. healthy tissue and found that the expression of SCAMPs1-4 was upregulated in PAAD compared to normal tissue. In contrast, SCAMP5 expression was downregulated in PAAD. Moreover, the expression of SCAMPs1-4 was enhanced in PAAD cell lines according to Cancer Cell Line public database. Furthermore, the HPA, GEPIA databases and immunohistochemical analysis from 238 patients suggested that the loss of SCAMP1 led to improved overall survival (OS), whilst lower SCAMP5 levels led to a poorer OS. The univariate and multivariate analysis showed that SCAMP1 and SCAMP5 expression were independent prognostic factors of PAAD. In addition, the cBioPortal for Cancer Genomics, LinkedOmics datasets, and the GEPIA were used to identify the co-expression genes of SCAMP1,5 and the correlation between SCAMPs members. We conclude that SCAMPs 1 and 5 significantly represent promising diagnosis and prognostic biomarkers.

High Expression of COL17A1 Predicts Poor Prognosis and Promotes the Tumor Progression via NF-κB Pathway in Pancreatic Adenocarcinoma.

COL17A1 (collagen type XVII alpha 1 chain) is known to be upregulated and has a prognostic role in many malignancies, as well as contributing to cell proliferation, apoptosis, and invasion. However, little knowledge is available on the expression and prognostic value of COL17A1 in pancreatic adenocarcinoma (PDAC). In our study, we searched the public database and found that mRNA and protein levels of COL17A1 are commonly upregulated in PDAC tissues. The immunohistochemical analysis conducted by us revealed enhanced expression of COL17A1 protein in 169 PDAC samples compared with that in 67 adjacent normal tissues. We also observed a significantly positive correlation between COL17A1 expression and lymph node metastasis (p < 0.0001), TNM clinical stage (p < 0.0001), and pathology differentiation (p < 0.01). The KM-plot results indicated that PDAC patients with a high COL17A1 expression have a poorer overall survival (p < 0.001) than those with a low COL17A1 expression. The result of the Cox regression analysis of multivariate data suggested COL17A1 is an independent prognostic indicator of PDAC patients' overall survival. CCK-8, wound healing, and transwell assays suggested that COL17A1 knockdown markedly inhibited tumor proliferation and invasion in PDAC cells, and cells with COL17A1 overexpression had a prominently higher proliferative and invasive capacity. Knockdown of COL17A1 significantly upregulated the apoptosis rate. We deduce that upregulated COL17A1 activated the NF-κB pathway in PDAC cells. In summary, our studies showed the prognostic value of COL17A1 in PDAC and that COL17A1 may act as a molecular therapeutic target for PDAC treatment.

Primary prophylaxis for venous thromboembolism in ambulatory cancer patients: a systematic review and network meta-analysis.

BACKGROUND: Ambulatory cancer patients carry a high risk of venous thromboembolism (VTE). However, the optimal prophylaxis strategy remains controversial. This meta-analysis compared the effectiveness and safety of apixaban, rivaroxaban, low molecular weight heparin (LMWH), semuloparin, aspirin, and warfarin for the prevention of VTE in ambulatory cancer patients. METHODS: A systematic review and network meta-analysis was performed. PubMed, the Cochrane Central Register of Controlled Trails (CENTRAL) and EMBASE electronic databases were searched from inception to 26 April 2019. In the meta-analysis, 19 randomized controlled trials (RCTs) in ambulatory cancer patients administrated venous thromboprophylaxis agents were included. The primary outcome was the risk of VTE. Safety outcomes included the occurrence of major-bleeding. Two investigators identified the studies and performed data extraction. A network meta-analysis was performed and agents were ranked using cumulative ranking (SUCRA) probabilities. RESULTS: We identified 19 studies, including 11,430 patients comparing 10 interventions. Compared to placebo controls, apixaban (5 mg) showed the highest efficacy for the prevention of VTE [odds ratio (OR) 0.36, 95% confidence interval (CI): 0.18-0.71, SUCRA=69.5] and was more effective than LMWH (OR 0.5, 0.39-0.63; SUCRA=52.1) or warfarin (OR 0.75, 95% CI: 0.35-1.59; SUCRA=25.6). Moreover, the safety of apixaban (5 mg) (OR 1.41, 95% CI: 0.33-5.93; SUCRA=58.5) was higher than LMWH (OR 1.96, 95% CI: 0.99-3.86; SUCRA=44.1) or warfarin (OR 3.06, 95% CI: 1.03-9.08; SUCRA=29.1). There were no significant differences between placebo and experimental groups in terms of patient deaths. CONCLUSIONS: Anticoagulation therapies in ambulatory cancer patients can significantly reduce the risk of VTE. However, this protective effect was associated with a significantly increased risk of major bleeding. Apixaban at the appropriate dose can decrease the risk of VTE without increasing the bleeding risk. These findings require validation in larger study cohorts.

Ethnobotanical survey and evaluation of traditional mosquito repellent plants of Dai people in Xishuangbanna, Yunnan Province, China.

ETHNOPHARMACOLOGICAL RELEVANCE: Dengue is one of the most important pervasive diseases in many regions of the world, including China. There is an urgent need for new repellents, including plant derivatives, due to the resistance, toxicity, and non-degradability of synthetic insecticides. Traditional plant-based remedies may provide potential avenues for developing new strategies. AIMS OF THE STUDY: The aims of this study were to 1) document the traditional mosquitoes repellent plants used by the Dai people of Xishuangbanna, China; 2) screen out new efficient mosquito repellent plants as candidates for further study. MATERIALS AND METHODS: During the period August 2016 to July 2017, five field surveys were conducted in 16 villages of Xishuangbanna. A total of 81 informants (44 males and 37 females) were interviewed using semi-structured questions to collect detailed information on the plants they use to prevent mosquito bites. Ten plants with higher popularity and larger resource were collected and extracts were prepared by hydro-distillation or with petroleum ether. Extracts were tested for adult Aedes albopictus repellency using a human-bait cage. Firstly, repellency was determined as the Minimum Effective Dosage (MED) per minute at which 1% of the mosquito bite through the treated cloth. Secondly, five plant extracts with lower MEDs were tested the repellent longevity of different concentrations. RESULTS: Eighteen plants were documented as being used in traditional remedies against mosquitoes. The methods for controlling mosquitoes were diverse: direct burning was used for most plants (16 species), followed by smearing (5 species), and placing (5 species). Laboratory analyses confirmed that ten plants did exhibit mosquito repellent activity. Of them, Artemisia indica, Nicotiana tabacum, Blumea balsamifera, Vitex trifolia, and Chromolaena odorata showed good mosquito repellency with MEDs of 0.015, 0.061, 0.090, 0.090, and 0.105 mg/cm2, respectively. The protection rate provided by A. indica is also the highest among five plants. Although it provides complete protection time of only 30 min at 0.45 mg/cm2 concentration, its repellency within 2 h is not significantly different from that of DEET. CONCLUSION: Dai villagers in Xishuangbanna have a rich, diverse and scientific knowledge of plant-based mosquito repellents. Laboratory experiments screened out several plants as candidates for mosquito repellents, of which Artemisia indica was the most promising candidate plant.

Acquired tamoxifen resistance is surmounted by GW8510 through ribonucleotide reductase M2 downregulation-mediated autophagy induction.

Tamoxifen resistance is a major roadblock in the treatment of patients with breast cancer. Ribonucleotide reductase M2 (RRM2) was found to be involved in acquired resistance of breast cancer cells (BCCs) to tamoxifen. Here, we used GW8510, which has been identified as a potential RRM2 inhibitor, to evaluate the effect of RRM2 inhibition on reversing resistance of BCCs to tamoxifen and investigate its mechanisms. We showed that RRM2 overexpression played a key role in the development of acquired tamoxifen resistance in BCCs through downregulation of autophagy level. Combination treatment with tamoxifen and GW8510 significantly inhibited survival of the tamoxifen-resistant BCCs through induction of autophagic cell death compared to either of the two drugs. Furthermore, combination of tamoxifen and GW8510 resulted in marked growth inhibition of tamoxifen-resistant BBC xenograft tumor in vivo compared to tamoxifen or GW8510 alone. In conclusion, tamoxifen in combination with GW8510 can overcome acquired tamoxifen resistance in BCCs and may be a rational therapeutic approach against breast cancer with high RRM2 expression.

PLS3 predicts poor prognosis in pancreatic cancer and promotes cancer cell proliferation via PI3K/AKT signaling.

Plastin-3 plays a key role in cancer cell proliferation and invasion, but its prognostic value in pancreatic cancer (PACA) remains poorly defined. In this study, we show that PLS3 messenger RNA is overexpressed in PACA tissue compared with normal tissue. We accumulated 207 cases of PACA specimens to perform immunohistochemical analysis and demonstrated that PLS3 levels correlate with T-classification (p < .001) and pathology (p < .001). Furthermore, overall survival rates (p < .001) in tumors with high PLS3 expression were poor, as assessed through Kaplan-Meier survival analysis. PLS3 was found to be an independent prognostic factor for PACA through multivariate Cox regression analysis. Moreover, we found that PLS3 enhances the proliferation and invasion of tumor cells as assessed through Cell Counting Kit-8, wounding healing assays, and Transwell assays. The upregulation of PLS3 also led to enhanced phosphatidylinositol-3 kinase/protein kinase B signaling in PACA cells. These data suggest that PLS3 is a biomarker to estimate PACA progression and represents a molecular target for PACA therapy.

Ethnobotanical survey of plants traditionally used against hematophagous invertebrates by ethnic groups in the mountainous area of Xishuangbanna, Southwest China.

Hematophagous invertebrates such as mosquitoes, leeches, mites, ticks, lice and bugs cause various problems for humans. Considering reports on insecticide resistance and requirements for improved environmental and toxicological profiles, there is a continuing need to discover and develop new insecticides and repellents. Ethnobotanical surveys of traditional plant-based repellents provide a direct method of identifying plants for potential use. During five field surveys in Bulang, Jinuo and Lahu villages between August 2018 and July 2019, semi-structured interviews were conducted with 237 informants (151 male, 86 female; mean age 63). Frequency of citation, use value, informant consensus factor and Jaccard index were employed to statistically analyze the collected data. A total of 709 use reports relating to 32 plant species and 71 remedies were collected. Similarities and differences between the three groups, as well as the Dai and Hani of Xishuangbanna, who were studied earlier, were shown through network analysis. These five ethnic groups living in the same area have a common understanding of traditional botanical knowledge against hematophagous invertebrates, but each group also possesses unique knowledge. Recording and protecting this traditional knowledge is potentially useful for protecting this cultural diversity and related biodiversity and can also have important practical applications. In this study, traditional knowledge provided us with many new potential plants for follow-up research for the development of new insecticides and repellents, among which Artemisia indica, Nicotiana tabacum and Clausena excavata are the most promising.

Coronary Atherosclerotic Plaque Volume Quantified by Computed Tomographic Angiography in Smokers Compared to Nonsmokers.

RATIONALE AND OBJECTIVES: We sought to compare the prevalence and volume of lipid plaque, fibrous plaque, and calcified plaque in patients with smokers versus nonsmokers. MATERIALS AND METHODS: We studied consecutive patients suspected of coronary artery disease and who underwent coronary computed tomography angiography. A structured interview and review of existing clinical data was conducted before computed tomography angiography to collect information on demographic characteristics, the presence of cardiovascular risk factors. The volume of lipid, fibrous, and calcified plaque were automatically calculated and marked in different colors according to predefined Hounsfield unit thresholds. The prevalence and volume of plaques were compared between smokers and nonsmokers. RESULTS: Overall 6380 patients (3351 men and 3029 women, mean age 55.35 years) were finally analyzed, of whom 2075 (32.5%) were smokers, and 4305 (67.5%) were never smokers. The prevalence of any plaque in smokers was significantly higher compared to never smokers (47.7% vs. 32.3%, p < 0.001). Smoking was an independent risk factor of the presence of any plaque after correcting for age, gender, body mass index, hypertension, dyslipidemia, diabetes, and family history in a multivariate model (odds ratio = 1.250 (1.088-1.437), p = 0.002). The volume of lipid plaque, fibrous plaque, calcified plaque, and total plaque in smokers was significantly greater than nonsmokers (p < 0.001). CONCLUSION: The prevalence and volume of lipid plaque, fibrous plaque, and calcified plaque were significantly higher in smokers versus never smokers.

Homogeneous Metal Nitrate Hydroxide Nanoarrays Grown on Nickel Foam for Efficient Electrocatalytic Oxygen Evolution.

Developing facile routes for fabricating highly efficient oxygen evolution reaction (OER) electrocatalysts is in great demand but remains a great challenge. Herein, a novel molten salt decomposition method to prepare 3D metal nitrate hydroxide (MNH, M = Ni, Co, and Cu) nanoarrays homogenously grown on different conductive substrates, especially on nickel foam (NF) for OER applications, is reported. Compared with the as-prepared CoNH/NF and CuNH/NF, NiNH/NF presents a superior electrocatalytic OER activity and stability in an alkaline solution, with a very low overpotential of only 231 mV versus a reversible hydrogen electrode to deliver a geometrical catalytic current density of 50 mA cm-2 and a low Tafel slope of 81 mV dec-1 , outperforming most reported transition metal compound catalysts. Structural investigation after the OER process reveals the morphology integrity of the nanoarrays but the formation of metal oxyhydroxide (for NiNH and CoNH) or oxide (for CuNH) as the likely real active species. These metal nitrate hydroxide non-noble metal electrocatalysts can be prepared by an economical and simple method, with enhanced intrinsic activity and long-term stability and durability, which might be new candidates for energy conversion and storage applications.

Identification of lncRNAs and Their Functional Network Associated with Chemoresistance in SW1990/GZ Pancreatic Cancer Cells by RNA Sequencing.

Drug resistance is a major problem in the treatment of pancreatic cancer (PC). Long noncoding (lnc)RNAs modulate a variety of cellular processes. This study was carried out to identify lncRNAs that are differentially expressed in drug-resistant PC by next-generation RNA sequencing. We identified 205 differentially expressed lncRNAs (DELs) and 847 differentially expressed mRNAs (DEMs) in a comparison of gemcitabine-resistant and -sensitive SW1990 human PC cells. The expression levels of 12 randomly selected lncRNAs were confirmed by quantitative real-time PCR. A total of 55 and 99 DEMs were predicted to be targeted by the DELs through cis and trans mechanisms, respectively. The DEMs were significantly enriched in the Gene Ontology terms cell part, binding, and cellular processes, and a Kyoto Encyclopedia of Genes and Genomes analysis showed that they were associated with metabolic pathway, pathways in cancer, insulin resistance, microRNAs in cancer, and phosphotidylinositol 3-kinase-Akt signaling pathway. A coexpression network revealed a hub comprising lncRNAs (MIR210HG, SNHG1, and LOC729970) and mRNAs (RAB3D, DDX17, and SPNS2) that presumably mediate drug resistance in PC. The identified lncRNAs can serve as diagnostic or prognostic biomarkers and therapeutic targets for PC.

Marital status independently predicts pancreatic cancer survival in patients treated with surgical resection: an analysis of the SEER database.

Marital status is an independent prognostic factor for survival in several cancers. To determine if that is also true for pancreatic cancer after surgical treatment, we examined 13,370 cases of pancreatic cancer reported to the Surveillance, Epidemiology, and End Results (SEER) database between 1988 and 2012. We found that patients who were widowed at the time of diagnosis were more likely to be female, a high percentage were elderly, a high ratio were diagnosed in early years, and a high proportion of tumors were located at the head of the pancreas (P < 0.05). Marital status was confirmed to be an independent prognostic factor in both univariate and multivariate analyses (P < 0.05). In those with localized disease, 5-year pancreatic cancer cause-specific survival was 6.5% lower in widowed patients than married ones (38.6% vs. 32.1%), though this difference was not significant in a multivariate analysis (P = 0.084). In those with regional disease or distant metastasis, univariate and multivariate analyses indicated marital status to be an independent prognostic factor (P < 0.05). Thus marital status is an important prognostic factor in pancreatic cancer, and widowed patients are at greater risk of death than others.

CIP2A down regulation enhances the sensitivity of pancreatic cancer cells to gemcitabine.

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein which participates in inhibiting tumor apoptosis in pancreatic cancer cells. Using immunohistochemical staining, we investigated the expression of CIP2A protein in 72 cases of human pancreatic ductal adenocarcinoma (PDAC) tissue and 27 cases of adjacent normal pancreatic tissue. The positive rate of CIP2A protein expression in pancreatic cancer tissue was70.83 %, which was significantly higher than that in adjacent non- cancerous pancreatic tissue (11.11%). The expression of CIP2A was found to be correlated with TNM stage, but not correlated with age, gender, tumor location, smoking status, alcohol consumption, diabetes, high blood pressure, BMI, tumor size, lymph node metastasis or distant metastases. Kaplan- Meier survival analysis showed that patients with positive CIP2A protein expression had a lower overall survival rate than patients without CIP2A expression. COX regression analysis indicated that expression of CIP2A was an independent prognostic factor for pancreatic ductal adenocarcinoma. In addition, down-regulation of CIP2A inhibited cell proliferation and increased sensitivity to gemcitabine in pancreatic cancer cells by decreasing AKT signaling pathway. Our results indicated that down-regulation of CIP2A could be a novel therapeutic strategy for pancreatic cancer.

MiR-125a regulates chemo-sensitivity to gemcitabine in human pancreatic cancer cells through targeting A20.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly human malignant diseases and the sixth leading cause of cancer-related deaths in China. Gemcitabine is the only first-line chemotherapeutic agent used for the palliative treatment of patients with PDAC, but chemo-resistance limits their efficacy. Here, we showed that miR-125a was up-regulated in chemo-resistant SW1990GZ cells when compared with SW1990 cells. Over-expression of miR-125a increased the chemo-resistance to gemcitabine in SW1990 cells, while down-regulation of miR-125a in SW1990GZ cells increased chemo-sensitivity to gemcitabine. By using bioinformatics analysis tool (Targetscan), the 3' untranslated region (3'UTR) of A20 gene was found to be a target of miR-125a. Luciferase reporter assay further confirmed that A20 3'UTR is a direct target of miR-125a. Over-expression of A20 in SW1990 cells increased chemo-sensitivity to gemcitabine, while knockdown of A20 in SW1990 cells promoted the chemo-resistance to gemcitabine. Finally, the expression level of miR-125a in pancreatic cancer tissues from chemo-sensitive patients was significantly lower than that from chemo-resistant patients, and was inversely correlated with the A20 mRNA levels. In conclusion, our results suggest that miR-125a promotes chemo-resistance to gemcitabine in pancreatic cells through targeting A20, which may provide novel therapeutic targets or molecular biomarkers for cancer therapy and improve tumor diagnosis or predictions of therapeutic responses.

The significance of aortic valve calcification in patients with bicuspid aortic valve disease.

Bicuspid aortic valve (BAV) is a common congenital heart disease. Our study was to analyze clinical features of BAV and evaluate whether aortic valve calcium score (AVCS) was a reliable marker for aortic stenosis (AS) in patients with BAV. 101 patients with BAV who both underwent echocardiology and cardiac computed tomography (CT) scan in our institution were included. Basic clinical data, haemodynamic feature, aortic valve and coronary calcium score were collected and compared among patients with different valve function and different degree of AS. Risk factors related to severe AS were evaluated by logistic regression, and a receiver operative characteristic curve was used to determine the cutoff calcium score greater than which the diagnosis of severe AS was optimized. Patients with aortic regurgitation (AR) were younger and demonstrated larger aortic annulus and sinus compared with patients with other valve dysfunction. Aortic valve calcium score was higher in patients with AS than with AR. For patients with different degree of AS, there were statistical significances in the value of age, aortic valve calcium score and coronary calcium score. AVCS was positively related to severe AS with an odd ratio of 1.286 (95% CI 1.099-1.504) by every 300 points increase. AVCS was also a strong predictor for severe AS with area under the curve 0.855 with a cutoff value of 897 (sensitivity 86.7%, specificity 72.2%). Conclusively, aortic calcium score calculated by quantitative CT is a reliable marker in evaluating severity of AS.